The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

Abstract

This study compares Breast Cancer 1 (BRCA1) and excision repair cross complementation group 1 (ERCC1) expression as predictive markers and evaluates the in vitro enhancement of platinum sensitivity using targeted agents in sporadic ovarian cancer (OC). A retrospective study was performed of advanced stage OC patients receiving platinum-based chemotherapy. BRCA1 and ERCC1 mRNA expression was determined from frozen tissue of 51 patients. Median overall survival (OS) was longer for patients with lower BRCA1 vs. higher BRCA1 (46 vs.33 months, p 5 0.03). High BRCA1 was predictive of poorer OS specifically in patients with residual disease (RD) <2 cm (p 5 0.03). There was a non-significant association for patients with lower ERCC1 and RD <2 cm in favor of improved OS and time to progression. Patients who expressed higher levels of both BRCA1 and ERCC1 mRNA had a shorter OS compared to patients with lower levels of either or both transcript (33 vs.46 months, p 5 0.04). When Cox proportional modeling was used by representing BRCA1 and ERCC1 mRNA expression as a continuous variable, both emerge as potential predictors of survival. OC cell lines were exposed to chemotherapy in combination with DNA repair pathway inhibitors and cell viability was assessed. In vitro histone deacetylase (HDAC) inhibition increased the sensitivity of A2780s/cp cells to cisplatin and carboplatin but not to taxol, coincident with a significant decrease in BRCA1 and ERCC1 expression, suggesting that this compound directly targets DNA repair. In summary, this study shows that low BRCA1 and ERCC1 expression correlate with improved survival in advanced OC and HDAC inhibition induces synergistic cytotoxicity with platinum in vitro. ' 2008 Wiley-Liss, Inc.Key words: BRCA1; ERCC1; sporadic ovarian cancer; DNA repair; predictive marker Epithelial ovarian cancer (OC) is generally diagnosed at advanced stage resulting in a 5-year survival of only 20-30%. The standard treatment of OC is surgical debulking followed by platinum and taxane chemotherapy. Although 70% of patients with advanced disease initially respond to the first-line regimen, early recurrences and platinum resistance are common obstacles in the management of this disease. Identifying reliable predictors of response and the use of novel therapeutic agents to enhance platinum efficacy are needed to improve the management of OC. Platinum resistance is multifactorial, 1 and an important mechanism of resistance is increased tolerance to platinum-DNA damage and enhanced repair of damaged DNA. In a variety of malignancies including OC, enhanced expression of the DNA repair proteins, Breast Cancer 1 (BRCA1) and excision repair cross complementation group 1 (ERCC1), have correlated with resistance to platinum. [2][3][4][5][6] In vitro models have shown that targeting the expression of both BRCA1 and ERCC1 sensitizes cells to platinum-based chemotherapeutic agents, suggesting a potential clinical application to help overcome platinum resistance in OC.Mutations in the BRCA1 tumor suppressor gene are ...

Predictive Value of Excision Repair Cross-complementing Rodent Repair Deficiency Complementation Group 1 and Ovarian Cancer Risk

“…However, we did not found an significant association between the two polymorphisms in ERCC1 gene, C8092A and T19007C, and the risk of ovarian cancer in a Chinese population. Our finding is different with previous study regarding the ERCC1 gene and ovarian cancer risk (Krivak et al, 2008;Weberpals et al, 2009;Avraam et al, 2011). One previous study was from American population showed the ERCC1 C8092A gene polymorphism is associated with the increased risk of ovarian cancer and clinic outcome.…”

“…One previous study was from American population showed the ERCC1 C8092A gene polymorphism is associated with the increased risk of ovarian cancer and clinic outcome. Another two previous studies with a significant association between ERCC1 polymorphism and the risk of ovarian cancer risk were from Greece and Canada with a relatively large sample sizes (Weberpals et al, 2009;Avraam et al, 2011). Another study conducted in Chinese population regarding the prognosis of ovarian cancer and ERCC1 gene polymorphisms also showed a significant association (Lin et al, 2010).…”

Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy

“…ERCC1 expression levels are inversely correlated with the response of cancers to platinum-based chemotherapy and have been widely recognized as a biomarker for potential chemoresistance in ovarian cancer. 21,41,42 EGR1 and MIR152 expression levels in ovarian cancer tissues were inversely correlated with ERCC1 expression, which further confirmed their roles in chemoresistance. It is noted that the direct relationship between EGR1 and MIR152 expression, and chemosensitivity should be investigated when more relevant clinical data become available in the future.…”

New developments in treatment of ovarian carcinoma: focus on trabectedin

“…Patients with low BRCA1 mRNA levels had significantly longer overall survival (P = 0.0297) and progression-free survival (P = 0.0427) than those with high BRCA1 levels, thereby confirming the prognostic value of BRCA1 expression in patients with ovarian carcinoma. 39 A trend (P = 0.0765) for longer overall survival (but not progression-free survival) was found for patients with high ERCC1 expression levels. No significant differences in progression-free survival or overall survival emerged for low or high XPD expression levels.…”